Tomoxiprole, 2-(4-methoxyphenyl)-3-(1-methylethyl)-3H-naphth[1,2-d] imidazole (formerly indicated as MDL 035) is a compound belonging to the class of the cycloxygenase 2 inhibitors, with analgesic, antinflammatoriry, antiarthritis activity The efficacy of tomoxiprole against said disorders has been demonstrated in animal studies. In contrast to most clinically used drugs, active doses of the compound are devoid of ulcerogenic activity (P. Schiatti et al. Arzneim-Forsch/Drug Res 1986, 36, 102-109; See also EP 0 012 866 A1)
Pharmacokinetics studies demonstrated that a substantial percentage of the tomoxiprole orally administered is absorbed and gives adequate concentrations in the blood lasting several hours. However the absorption is slow, attaining the maximum concentration of the substance in the blood over one hour after administration (A. Bernareggi et al. J. Liquid Chromatography 1984, 7, 2093-2101). Due to its high lipophilicity tomoxiprole unless ionized is practically insoluble in water. It is a weak base: at pH values lower than 2 is partially ionized and moderately soluble in water. The rate of dissolution is slow, due to physical properties of the crystal form (Form I) in which the compound has been so far obtained. The XRPD of the crystals are shown in FIG. 1.
Since the molecule exhibits good membrane permeation characteristics, its slow solution rate in gastric fluids appears to be responsible for its slow absorption and consequently of a delayed onset of action.
The main predicted use of tomoxiprole is as analgesic, for the management of diseases as dental pain, post traumatic pain, headache and dysmenorrhoea. A rapid onset of the therapeutical action with consequent relieve of the pain is an important aspect of the medical treatment of said diseases.
The present invention relates to different approaches to obtain a faster solution rate of the molecule in conditions mimicking gastric juice, and hence a more rapid absorption of the drug.
First Approach: Amorphous Form or Novel Crystal Forms
The slow dissolution rate of tomoxiprole Form I crystals (illustrated in FIG. 2) is due to their physical characteristics: low surface wettability (water contact angle 81° at any pH) and a high crystal lattice stability, as demonstrated by the melting point (165° C.). Attempts at obtaining different crystal forms consisting in dissolving the sample in a solvent and inducing precipitation by cooling or concentrating the solution failed. Several solvents were used, such as acetone, anhydrous ethanol, methylene chloride. In all the cases the crystal Form I, melting point 165° C., (determined by DSC, see graph reported in FIG. 5) was observed.
Surprisingly, whereas from anhydrous ethanol Form I crystallized, from ethanol 96% a solid mainly consisting of a new form (Form II) was obtained. Pure crystals of the new form were prepared by dissolving the sample in methanol, adding water to precipitate the compound and removing methanol under vacuum. Form II in DSC is characterized by a melting point 155° C., followed by recrystallization into Form I and subsequent melting at 165° C. As predicted by the DSC results, Form II is unstable and even at room temperature slowly transforms into Form I.
It is a common knowledge that the amorphous form of a product have a dissolution rate much faster than that of crystal structure. This is due to the fact that amorphous forms have larger surface area and their lattice energy is much weaker than in crystals. Said factors influence the dissolution rate but not the absolute solubility of the different physical structures, which depends on other factors, mainly the ionization degree of the substance.
Attempts of preparing the amorphous form were performed by dissolving the sample in a solvent and obtaining a rapid precipitation by slow addition of a solvent in which tomoxiprole is not soluble. By addition of water to ethanol or acetone solutions, or of petroleum ether to chloroform or dichlorometane solutions, crystals of Form I were always produced. By dissolving tomoxiprole in methanol and addition of water the above described crystals of Form II were obtained.
The only positive result, formation of an amorphous form, was obtained by a different technique, consisting of the instant evaporation of a tomoxiprole solution. A solution of tomoxiprole in ethanol was flash evaporated by spray drying. A vitreous amorphous layer of tomoxiprole was obtained. However, the substance was highly instable and in a short time transformed into Form I crystals. Hence it appears that the amorphous form of the compound is intrinsically unstable.
Second Approach: Complexes of Tomoxiprole with Cyclodextrins
Scientific literature and patents report many examples of increasing the water solubility of drugs by forming complexes or adducts of compounds with cyclodextrins. However, in general, significantly enhanced solubility is obtained only with high molar ratios cyclodextrin/active substance. In many examples, solutions of over 10% (wt/vol) of cyclodextrin are used to obtain a significant solubility of the drug (T. Loftsson et al. J. Pharm. Sc. 1996, 85, 1017-1025). Said drug/cyclodextrin ratios are suitable for parenteral administration or acqueus eye drops but the high relative amount of cyclodextrin respect to drug makes these technically unsuitable for the preparation of tablet or capsules for oral administration.
In industrial pharmaceutical practice and in commercial use, including patients compliance, limits are imposed to the size of orally delivering devices. In general, the total content of active ingredients of a tablet or capsule, preferably, should not exceed the weight of one gram.
Another reported property of drug/cyclodextrin complexes is stabilization of the active product crystalline or amorphous solid state forms.
However, the state of the art shows that in most cases the stabilization of an amorphous form of a substance is obtained with a molar ratio cyclodestin/substance higher than 2. As an example in US 2006/0135473 is reported that the complex beta-cyclodextrin/piroxicam with molar ratio 2.5:1 shows the best stabilization and dissolution rate performance.
Another teaching derivable from the state of the art is that in several cases it is not possible to obtain a substance/cyclodextrin adducts were the substance is totally present in amorphous form (M. N. Reddy et al. AAPS J. 2004, 6, 68-86; S. Rawat et al. Eur. J. Pha.r Biopharm. 2004, 57, 263-267). For instance, in said documents it is shown that several different methods of preparing a celecoxib/beta-cyclodextrin complex yielded only mixtures of crystalline celecoxib and amorphous adducts. Moreover, not always the formation of a complex of active substance/cyclodextrin stabilizes the amorphous form of the active substance (F. Hirayama et al. Pharm. Res. 1994, 11, 1776-70, PubMed 7899242). In this document it is disclosed that the complex nifedipine/2-hydroxypropyl-beta-cyclodextrin, rather than to stabilize the substance in its amorphous form, accelerates its conversion to a crystalline form. EP 1219306 A discloses compositions comprising cyclodextrins and NO-releasing drugs where the drug is bound to a NO-releasing radical.
Although tomoxiprole is mentioned among an extremely large group of compounds which may be bound to a NO-releasing radical and then combined with cyclodextrin, this document does not contain any disclosure of a complex and a method for the preparation thereof where the molar ratio between the active substance and cyclodextrin has a predetermined value and does not provide any indication or hint or suggestion to preparing a stable complex where tomoxiprole is contained in a molar ratio near 1:1 with 2-hydroxypropyl-beta-cyclodextrin.